Synthesis of pyridoxine



Patented June 8, 1954 SYNTHESIS OF PYRIDOXINE Philip G. Stevens, OldGreenwich, Conn, assignor to General Aniline & Film Corporation, NewYork, N. Y., a corporation of Delaware No Drawing. Application February6, 1951, Serial No. 209,700

6 Claims. 1

This invention relates to a process for the preparation of pyridoxine(vitamin B) and intermeoliates therefor.

In accordance with this invention, 2-butanonediol-L4 or an etherthereof, or 2-butynediol-lA or its ethers, which yield the aforesaid.Z-butanonediol-Le and its ethers on hydration, is condensed withamethyliminopropionitrile or its tautomer,a--methyieneaminopropionitrile, or a compound such asa-methy1olaminopropionitrile which yields a-methyleneaminopropionitrileon dehydration, whereby there is formed 2- methyl-3-aminoi,5dimethylolpyridine or an ether thereof such as the monoor dimethylether, or the corresponding 4,5-epoxydimethyl derivative, said ethersyielding pyridoxine after diazotization and replacement of the aminogroup by hydroxyl, and thence by hydrolysis in accordance with knownmethods.

The intermediate 2-butynediol-l,4. is obtained by condensingformaldehyde with acetylene. Upon hydration of this acetylenic glycol inthe presence of a mercuric salt, 2-butanonediol-i,4 is obtained, which,under dehydrating conditions, forms 3-ketotetrahydrofuran (i. e., acyclic diether of 2-butanonediol-ifl is obtained); 3-ketotetrahydrofuran can also be obtained from 2-butanonediol-1,4 byhydrogenating the latter to butanetriol, dehydrating this to3-hydroxytetrahydrofuran, followed by dehydrogenation. Monoand diethersoi Z-outanonediol-IA (e. g. the monoand dimethyl ethers or other loweralkyl ethers) can be obtained by conventional methods from the freeglycol. .Z-butynedioLlA can be converted to the corresponding monoordimethyl ether by conventional methods. The latter ethers can behydrolyzed in the presence of a mercuric salt to the correspondingethers of 2-butanonediol-1A. All of the aforesaid diols and their loweralkyl (e. g. methyl or ethyl) monoand diethers, or the cyclic ether, canbe used as intermediates for the synthesis of this invention.

The other intermediates for the present process can be obtained bymixing formaldehyde in aqueous or alcoholic solution witha-aminopropionitrile to form the corresponding a-methyleneaminoora-methylolaminop-ropionitrile; or by condensation of pyruvic nitrilewith methylamine at low temperature to form a-methyliminopropinonitrile.

In accordance with the preferred procedure of this invention,3-ketotetrahydrofuran is condensed with a.-methyliminopropionitrile toform 2 methyl-3-amino-4,5-epoxydimethyl-pyridine, as illustrated by thefollowing equations:

On diazotization of the resulting aminopyridine compound, and thermaldecomposition of the resulting diazo derivative, 2-methyl-3- hydroxy 4,5epoxydimethyl-pyridine is produced, in which the epoxydiinethyl radicalcan be hydrolyzed, e. g. by conversion with hydrochloric or hydrobromicacid to chloromethyl or bromomethyl groups, and the latter hydrolysed inaqueous alkali, to form pyridoxine (i. e., vitamin B5 orZ-methyl-B-hydroxy-4,5-dimethylolpyridine).

In similar manner, Z-butanone-lA-diol and its monoand dialkyl ethersreact with methyliminopropionitrile to form 2-rnethyl-3-amino-4,5-dimethylol-pyridine and its monoand dialkyl ethers. The latteraminopyridine com pounds, upon diazotization with nitrous acid andthermal decomposition of the resulting diazo group yield thecorresponding 2-methyl-3-hydroXyl,5-dimethylol-pyridine (pyridoxine), oralkyl ethers thereof, which can be readily hydrolyzed to pyridoxine.However, in the case of 2-methyl-3-amino4,5-dimethylol-pyridine, it isadvantageous to convert this compound to the corresponding cyclic ether(2-methyl-3-amino- 4,5-epoxydirnethyl-pyridine) by dehydration, beforediazotizing and decomposition of the diazo radical, and then tohydrolyze resulting 2- methyl-3-hydroXy-4,5-epoxydimethylpyridine topyridoxine, in order to facilitate recovery of the product in pure form.

Instead of a-methyliminopropionitrile, its tautomer, amethyleneaminopropionitrile can be employed in the reactions describedabove. a-Methylolaminopropionitrile, which yieldsamethyleneaminopropionitrile upon dehydration can also be employed insimilar manner.

The process of this invention is illustrated in the following examples,wherein parts are by weight unless otherwise indicated.

Example 1 62 parts of a-methyliminopropionitrile (obtained by passingmethylamine into pyruvic nitrile at room temperature) are mixed with 172parts of 3-ketotetrahydrofuran, and 1 part of an amine salt such aspiperidine acetate, or of an alkali nietalamine compound such as lithiummonoethylaniline. The mixture is agitated at 25 to 100 C. untilcondensation is substantially complete. The reaction mixture is pouredinto water and acidified with dilute sulfuric acid to a pH of 4 to 5.The resulting mixture, containing a sulfate of2-methyl-3-amino-4,5-epoxydimethylpyridine in aqueous solution isextracted, preferably by continuous treatment, with a substantiallywater-insoluble organic solvent such as benzene, petroleum ether,chloroform or trichloroethylene, to remove unreacted3-ketotetrahydroiuran and other neutral organic compounds. Uponevaporating the residual aqueous solution, the sulfate of2-*nethyl3-amino-i,5- epoxydimethyl-pyridine is obtained in solid form,and can be purified by recrystallization from aqueous alcohol solution.

As disclosed in my copending application Serial No. 202,404, filedDecember 22, 1950, the

resulting product can be diazotized and the diazo compound converted tothe corresponding hydroxyl compound by treatment with sodium nitrite indilute aqueous sulfuric acid at about 90 C., and after destruction ofexcess nitrous acid by addition of urea, the solution is neutralizedwith caustic soda and water evaporated, whereby2-methyl-S-hydroxy-4,5-epoxydirnethylpyridine separates in the form ofan oily layer. The evaporated residue is extracted with ether and theether evaporated from the extract, whereby 2methyl-3-hydroxy-l,5-epoxydimethyl-pyridine is obtained as a lightcolored oil. By heating this with hydrobroinic acid, the afore saidcompound is converted to the corresponding 4,5-bromomethyl derivative,which, upon hydrolysis with aqueous alkali, yields 2-methyl-3-hydroxy-4,5-dimethylol-pyridine(pyridoxine) Example 2 62 parts ofa-inethyliminopropionitrile are added to an aqueous solution of 172parts of 2- butynediol-iA and sufficient mercuric acetate is added toeffect hydration of the acetylenic alcohol to 2-outanone-L4-diol. 1 partof piperidine acetate is added, and the mixture is allowed to dine isconverted to 2-methyl-3-amino-4,5-epoxydimethyl-pyridine. The latter canbe purified as described in the preceding example, diazotized withsodium nitrite in dilute sulfuric acid, and the diazo compounddecomposed by heating at 90 C. Alternatively, thedimethylolaminopyridine compound can be diazotized without purificationin the presence of dilute sulfuric acid with similar thermaldecomposition. Z-nethyl- 3-hydroxy-4,5epoxydimethyl-pyridine is therebyobtained, which yields pyridoxine on hydrolysis as described in Example1.

Upon substituting an equivalent amount of the monoor dimethyl ether of2-butanone-1A- diol for the 3-ket0tetrahydrohuan in Example 1, or bysubstituting an, equimolecular amount of the monoor dimethyl ether ofZ-butyne-L idiol for the correspondi -g acetylenic alcohol in Example 2,the corresponding monoor dimethyl ether ofZ-methyl-B-amino-ij-dimethylol-pyridine can be obtained by theprocedures of the foregoing examples. These compounds can be similarlydiazotized and decomposed to the corresponding Z-methyl 3aminoifi-dimethylolpyridine monoor dimethyl others, and the latterhydrolyzed by the procedure indicated in Example 1 for conversion topyridoxine.

In each of the foregoing procedures, an equivalent amount ofa-methyleneaminopropionitrile, or the equivalent amount ofa-methylolaminopropionitrile can be substituted fora-methylliininopropionitrile to obtain similar results.

Variations and modifications which will be obvious to those skilled inthe art can be made in the procedures hereinbefore described withoutdeparting from the scope or spirit of the invention.

I claim:

1. A process for preparing an ether of2-methyl-3amino-4,5-dimethylolpyridinc, which comprises reacting anether of Z-butanone-L-i-diol containing 4 to 8 carbon atoms with amember of the group consisting of u-rnethyliminm, u.- methyleneamino anda-n1ethylolamino-propionitrile at condensation temperature.

2. A process for preparing 2-niethyl-3-amino- 4,5-dimethylolpyridine,which comprises reacting 2-butanone-L4-diol with a member of the groupconsisting of e-methylirnino-, a-methyleneaminm andu-methylolamino-propionitrile at condensation temperature.

3. A process for preparing Z-methyl-B-amino-4-,5-epoxydirnethylpyridine, which comprises reacting 3ketotetrahydrofuran with a-methyliminopropionitrile at 25 to 100 C. inthe presence of piperidine acetate.

4. A process for preparing 2-methyl-3-amino- 4,5-epoxydimethylpyridine,which comprises reacting E-ketotetrahydrofuran with amethylimincpropionitrile at 25 to 100 C. in the presence of an alkalimetal monoethylaniline.

5. A process for preparing 2-rnethyl-3-amino- 4,5-dimethylol-pyridine,which comprises reacting Z-butyne-lA-diol with a mercuric salt inaqueous medium and with u-methyliininopropionitrile at a temperaturefrom 25 to 100 C.

6. A process for preparing Z-methyl-B-amino- 4,5-epoxydimethylpyridine,which comprises reacting S-ketotetrahydroiuran with a member of thegroup consisting of a-inethylimino-, oc-l'IlQthyleneamino-, anda-methy10lamino-propionitrile at a temperature from 2 to 100 C.

References Cited in the file of this patent UNITED STATES PATENTS NumberName Date 2,272,198 Harris Feb. '10, 1942 2,333,493 Rigby Nov. 2, 1943

1. A PROCESS FOR PREPARING AN ETHER OF2-METHYL-3-AMINO-4,5-DIMETHYLOLPYRIDINE, WHICH COMPRISES REACTING ANETHER OF 2-BUTANONE-1,4-DIOL CONTAINING 4 TO 8 CARBON ATOMS WITH AMEMBER OF THE GROUP CONSISTING OF A-METHYLIMINO-, AMETHYLENEAMINO- ANDA-METHYLOLAMINO-PROPIONITRILE AT CONDENSATION TEMPERATURE.